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The MLL SET domain is a histone H3 lysine 4 mono‐methyltransferase that interacts with WDR5 in the pre‐SET ATA2 domain.
Author(s) -
Patel Anamika B.,
Dharmarajan Venkat,
Cosgrove Michael S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1026.3
Subject(s) - histone methyltransferase , histone h3 , methyltransferase , histone , methylation , microbiology and biotechnology , chemistry , histone methylation , biology , gene , biochemistry , dna methylation , gene expression
Di‐ and Trimethylation of histone H3 Lysine 4 (H3K4) are associated with transcriptional activation, and are deposited by a family of proteins sharing a conserved SET domain. One of the chief regulators of H3K4 methylation is the Mixed Lineage Leukemia protein (MLL), which is required for the regulation of Hox genes in hematopoiesis and development. MLL interacts with WDR5, RbBP5, and Ash2L to form a core complex of proteins that are required for the regulation of MLL’s H3K4 methylation activity. It has been suggested that WDR5 plays a central role in maintaining the structural integrity of the MLL core complex. However, it is not currently understood how WDR5 interacts with MLL and how it regulates MLL’S catalytic properties. Here we report on the hydrodynamic properties of WDR5 and an MLL SET domain construct consisting of residues 3745‐3969 (MLL3745). We show that MLL3745 forms a 1:1 hetero‐dimer with WDR5 with a dissociation constant (Kd) of 0.26 ± 0.02 ÂμM. Furthermore, this interaction requires conserved residues in the pre‐SET ATA2 region of MLL3745. We also show that the recombinant MLL SET domain is a mono‐methyltransferase, and that interaction with WDR5 does not change MLL’S product specificity, but does enhance MLL’S thermostability. These results reveal a new function for the pre‐Set ATA2 domain of MLL in that it is important for the recruitment of proteins that regulate the catalytic activity of the SET domain.